Ambrisentan is the International Nonproprietary Name (INN) of name (2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid, and has the CAS Nr 177036-94-1. It functions as an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is a drug indicated for use in the treatment of pulmonary hypertension.
The structure of Ambrisentan corresponds to formula (I):

Different processes for the preparation of Ambrisentan and its salts are known in the art.
Ambrisentan was first described in the patent family of U.S. Pat. No. 5,932,730-BASF. In this patent it is disclosed a resolution step on a laboratory scale of 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid using as resolving agents either L-prolinemethylester (cf. Example 10) or (S)-1-(4-nitrophenyl)ethylamine (cf. Example 11). In the first case the diastereoisomeric salt of the (R)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid is crystallized and separated off, and then from the mother liquor is subsequently isolated the (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid (35% yield from racemic—100% ee). In the second case, the corresponding diastereoisomeric salt is crystallized from methyl tert-butyl ether/acetone, and subsequently it is converted into the free acid (35% yield from racemic—99.8% ee).
Unfortunately, these resolution agents are extremely expensive and would not be preferable for large scale production. In addition, the methyl prolinate could not be completely recycled since free methyl prolinate tends to form diketopiperazines (cf. eg. R. Jansen et al., Organic Process Research & Development, 2001, vol. 5, pp. 16-22). On the other hand, in U.S. Pat. No. 6,559,338 from the same applicant it is stated that when this described reaction was scaled up, additional working steps became necessary in order to ensure a high optical purity as the diastereoisomeric salt with (S)-1-(4-nitrophenyl)ethylamine crystallized with difficulty and could not be filtered off readily. As a consequence, some of the mother liquor remained in the crystals together with the enantiomer to be separated off. Only when the crystals were additionally stirred in the tank together with fresh solvent, and when the crystals which had been filtered off once more had been copiously rewashed, could the required optical purity be obtained.
U.S. Pat. No. 6,559,338 describes a process of resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid by using an optically active base (S)-1-(4-chlorophenyl)ethylamine. In Example 1, the resolution process is carried out using tert-butylmethylether/methanol as solvents and one of the diastereomeric salts formed is separated off with a yield of 36% and an ee >99.5%. The filtration problem is reported to be resolved with this agent. However, this resolving agent is also very expensive and would not be preferable for large-scale production.
Other resolution processes have also been disclosed in the art. Thus, WO2012017441A1-NATCO Pharma Ltd discloses an improved process of resolution of 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid with (S)-1-(4-nitrophenyl)ethylamine (as U.S. Pat. No. 5,932,730). According to the Example, it is obtained a compound having a chemical purity of 99.97% and a chiral purity of 99.98% with a yield of 27.5% in this step of the global process.
WO2011004402A2-Cadila Healthcare Limited describes a process of resolution of the 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid by using a chiral amine, in particular, (S)-3-methoxyphenylethylamine or (R)-2,4-dichlorophenylethylamine, and the diastereoisomeric salts thus obtained can be directly used in the following step of alkylation to form Ambrisentan. According to the Examples, in the alkylation step N,N-dimethylformamide is used as solvent, which implies that the recovery of the chiral amine most probably will be difficult to carry out.
Finally, WO2010070658A2-MSN Laboratories Ltd also discloses a process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid, which comprises treating the racemic 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid compound with R(+)-phenyl ethyl amine in a chlorinated solvent to provide the R(+)-phenyl ethyl amine salt of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid. In Example 22 is exemplified the process which uses chloroform as solvent. The use of chlorinated solvents and, specially, chloroform are not convenient in the industry.
The (S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid is an intermediate useful not only to prepare Ambrisentan but also to prepare other endothelin receptor antagonists such as Darusentan, which is the compound (2S)-2-(4,6-dimethoxypyrimidin-2-yl)oxy-3-methoxy-3,3-di(phenyl)propanoic acid. From what is known in the art is derived that there is still a need of a new resolution process for 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid using cheaper chiral agents and safer solvents.